Ethers and thioethers having therapeutical activity, their preparation and pharmaceutical compositions containing them

ABSTRACT

Compounds of formula I ##STR1## wherein Ar is an optionally substituted phenyl ring; B is a single bond, a group --(CH 2  OCH 2 ) n  being n=1 or 2, a 2,4-disubstituted-1,3-dioxolane ring or a 2,4-disubstituted-1,3-thioxolane ring, R is a single bond, an optionally substituted methylene or ethylene group and T is 2-, 3- or 4-pyridyl, an optionally salified or esterified carboxy group or a carboxyamide group. Said compounds are useful in treatment of respiratory diseases.

The present invention concerns compounds endowed with mucolytic andantitussive activities.

The compounds of the invention have the following general formula I##STR2## wherein: Ar is an unsubstituted or polysubstituted phenyl ring;

B is selected in the group consisting of a valency bond, --(CH₂O--CH₂)_(n), and 1,3-dioxolan-2,4-diyl or 1,3-thioxolan-2,4-diyl radicalgroup which may be indifferently bonded to the remaining parts of themolecule by means of C(2) and C(4) carbons of the heterocyclic ring;

X is sulphur or oxygen;

T is a 2-, 3-or 4-pyridyl, carboxyl, --CO₂ R₆, --COR₆, --CO₂ NH₂,--CONRdRe, --CO--NH--CH(Rc)--CO₂ Ra or a di-(C₁ -C₄)-alkylamino-(C₁-C₄)-alkylaminocarbonyl-, hydroxy, (C₁ -C₄)- alkoxy-(C₁-C₄)-alkyl-aminocarbonyl-, di-(C₁ -C₄)-alkyl-amino-(C₁ -C₄)-alkoxy-(C₁-C₄)-alkyl -amino-carbonyl or 2-, 3-, 4-pyridylmethylamino -carbonylgroup;

R represents --(CH₂)_(n) --, --CH(R₄)--, --CH₂ --CH(NH₂)-- or --CH₂--CH(NH--CORa)-- group;

R₁, R₂ and R₃, that can be the same or different, are selected from thegroup consisting of hydrogen, hydroxy, (C₁ -C₅)-acyloxy, (C₁ -C₄)-alkyl,(C₁ -C₄)-alkoxyl, (C₂ -C₄)-alkenyl, halogen, (C₁ -C₅)-acylamino, phenyl,phenoxy, imidazol-1-yl, carboxyl, (C₁ -C₃)-alkoxy-carbonyl, carboxy-(C₁-C₄) -alkyl;

R₄ is (C₁ -C₄)-alkyl or a (C₂ -C₄)-alkenyl group;

Ra is hydrogen or a (C₁ -C₄) -alkyl group;

R₆ is a (C₁ -C₆)-alkyl group optionally substituted by (C₁ -C₆)-alkoxy,carboxyl, (C₁ -C₄)-alkylamino, di-(C₁ -C₄)-alkylamino, morpholin-N-yl,piperidin-1-yl, 4-(C₁ -C₄)-alkyl-piperazin-1-yl, (C₃ -C₆)-alkenyl,phenyl or phenyl-(C₁ -C₆)-alkyl groups;

Rc is hydrogen or a (C₁ -C₆)-alkyl, or (C₆ -C₁₄)-ar-(C₁ -C₄)-alkyl, orheteroalkyl group of a residue of a natural α-aminoacid, and

Rd and Re, which can be the same or different, are hydrogen, a (C₁-C₆)-alkyl optionally substituted by (C₁ -C₆)-alkoxy, morpholin-N-yl,piperidin-1-yl, 4-(C₁ -C₄)-alkyl-piperazin-1-yl, hydroxy-(C₁-C₄)-alkoxy-(C₁ -C₄)-alkyl or di-(C₁ -C₄) -alkylamin -(C₁-C₄)-alkoxy-(C₁ -C₄)-alkyl group or Rd and Re together with the nitrogenatom to which they are bonded form a heterocyclic ring selected from thegroup consisting of morpholin-N-yl, piperidin-1-yl and 4-(C₁-C₄)-alkyl-piperazin-1-yl.

In the scope of the invention are also included pharmaceuticallyacceptable salts, optical antipodes, i.e. the single enantiomers,mixtures of optical antipodes diasteroisomers and mixtures ofdiasteroisomers of compounds of formula I.

The above mentioned carboxy groups are optionally salified with anammonium or alkaline cation.

The term halogen is to be understood to mean fluorine, chlorine, bromineand iodine, but preferably bromine and chlorine.

The aralkyl radical can be phenyl-(C₁ -C₄)-alkyl or naphthyl-(C₁-C₄)-alkyl

A (C₁ -C₆)-alkyl, a (C₆ -C₁₄)-ar-(C₁ -C₄)-alkyl and a heteroalkylresidue of a natural α-aminoacid means for example N-alanyl, N-valinyl,N-phenylalanyl, N-methionyl or N-histidinyl.

More particularly the present invention concerns addition salts withpharmaceutically acceptable bases, when in the compounds of formula Ithere is a free carboxylic group and addition salts withpharmaceutically acceptable acids, when in the compounds of formula Ithere is a basic organic portion.

Typical examples of non-toxic and pharmaceutically acceptable bases areorganic bases, e.g. amines such as methylamine, dimethylamine,trimethylamine, ethylamine, diisopropylamine, N-methyl-N-hexylamine,tromethamine, cyclohexylamine, N-methyl-N-cyclohexylamine,α-phenylethylamine, β-phenylethylamine, N,N-dimethylethanolamine,N,N-dielhylethanolamine, ethylendiamine, piperidine, morpholine,piperazine, galactamine, N-methylglucamine, ephedrine, lysine, arginineand inorganic bases such as hydroxides of alkaline and alkaline-earthmetals, as well as zinc and aluminum hydroxides.

Typical examples of non-toxic, pharmacologically acceptable acids areorganic acids, such as acetic, formic, propionic, fumaric, tartaric,maleic, malic, malonic, benzoic, salicylic, 3,4,5-trimethoxybenzoic,methanesulphonic, benzenesulphonic, camphorsulphonic, lactic, aspartic,glutammic, L- or D-2-phenyl-thiazolidine-5-carboxylic acids, cystine andcysteine; and inorganic acids such as nitric, phosphoric, sulphuric,hydrochloric and hydrobromic acids.

According to the invention, alkyl, alkenyl, alkoxy groups may havelinear or branched chain.

Non-limitative examples of compounds of the invention are those whereinthe group ##STR3## is phenyl, 2-hydroxyphenyl, 2- or 4-methoxyphenyl,2-methoxy-4-allyl-phenyl, 3,4,5-trimethoxyphenyl,3,5-dimethoxy-4-hydroxyphenyl, 3,5-ditert.butoxy-4-hydroxyphenyl,4-acetamidophenyl, 4-ethoxycarbonylcarboxyamido-phenyl,4-(imidazol-1-yl)-2-allyl-phenyl. B is a single bond or a1,3-dioxolane-4,2-diyl, a 1,3-thioxolane-4,2-diyl,1,3-thioxolane-2,4-diyl or a 1,3-dioxolane-2,4-diyl group of theformulae: ##STR4## and X - R - T are one of the groups having the abovereported formulae.

Particularly preferred examples of compounds of the invention are:

ethyl 4-/4-(2-methoxyphenoxy)-methyl-(E) (1,3)-dioxolane-2-yl/-3-oxabutanoate;

3-oxa-4-/4-(2-methoxyphenoxy)-methyl-(E)-(1,3) dioxolane-2-yl/-butanoicacid;

3-oxa-4-/4-(2-methoxyphenoxy)-methyl-(Z)-(1,3) dioxolane-2-yl/-butanoicacid;

3-oxa-4-/4-(2-methoxyphenoxy)-methyl-(Z,E)(1,3)-dioxolane-2-yl/-butanoic acid;

3-oxa-4-/4-(3,5-ditert.butyl-4-hydroxyphenoxy)methyl(Z,E)-(1,3)-dioxolane-2-yl/ -butanoic acid;

3-oxa-4-/-(3,5-dimethoxy-4-hydroxyphenoxy)methyl(Z,E)-(1,3)-dioxolane-2-yl/-butanoic acid;

3-oxa-4-/4-(3,4,5-trimethoxyphenoxy)methyl-(Z,E)(1,3)-dioxolane-2-yl/-butanoic acid;

3-oxa-4-/4-(2-methoxy-4-allyl-phenoxy)-methyl-(Z,E)-(1,3)-dioxolane-2-yl/-butanoicacid;

3-oxa-4-/4-(4-methoxyphenoxy)methyl-(Z,E)-(1,3)-dioxolane-2-yl/-butanoicacid;

3-thia-4-/4-(2-methoxyphenoxy)methyl-(Z,E)-dioxolane-2-yl/-butanoicacid;

3-thia-4-/4-(2-phenoxy)methyl-(Z)-(1,3)-dioxolane-2-yl/- butanoic acid;

3-thia-4-/4-(4-methoxyphenoxy)methyl-(Z,E)-(1,3)-dioxolane-2-yl/-butanoicacid;

3-thia-4-/4-(2-methoxyphenoxy)methyl-(E)-(1,3)-dioxolane-2-yl/-butanoicacid;

3-thia-4-/4-(2-hydroxyphenoxy)methyl-(Z,E)-(1,3)-dioxolane-2-yl/-butanoicacid;

3-thia-4-/4-(3,4,5-trimethoxyphenoxy)methyl-(Z,E)-1,3)-dioxolane-2-yl/-butanoicacid;

3-thia-4-/4-(3,5-dimethoxy-4-hydroxy-phenoxy)methyl-(Z,E)-(1,3)-dioxolane-2-Yl/-butanoicacid;

3-thia-4-/4-(4-imidazol-1-yl-phenoxy)-methyl-(Z,E)(1,3)-dioxolane-2-yl/-butanoicacid;

3-thia-4-/4-(3,5-ditert butyl-4-hydroxy-phenoxy)methyl(Z,E)-(1,3)-dioxolane-2-yl/-butanoic acid;

3-thia-4-/-4-(4-acetamidophenoxy)methyl-(Z,E)(1,3)-dioxolane-2-yl/-butanoicacid;

3-thia-4-/4-(2-methoxy-4-allyl-phenoxy)methyl-(Z,E)-(1,3)-dioxolane-2-yl/butanoicacid;

2-(acetylammino)-4-thia-5/4-(2-methoxyphenoxy)methyl(Z,E)-(1,3)-dioxolane-2-yl/-pentanoic acid;

2-(acetylamino)-4-thia-5/4-(4-methoxyphenoxy)methyl-(ZE)-(1,3)-dioxolane-2-yl/-pentanoicacid;

2S-/4-(2-methoxyphenoxy)methyl-(Z,E)-(1,3)dioxolane-2-yl/-methylthio-propionyl-glycine;

3-thia-4/4-(2-methoxyphenoxy)methyl-(Z,E)-(1,3)-thioxolane-2-yl/-butanoicacid;

3-thia-4/4-(4-methoxyphenoxy)-methyl-(Z,E)-(1,3)-thioxolane-2-yl/-butanoicacid;

3-thia-4-/4-(3,4,5-trimethoxyphenoxy)methyl-(Z,E)-(1,3)-thioxolane-2-yl/-butanoicacid;

3-thia-4/4-(4-imidazol-1-yl)-phenoxy)methyl-(Z,E)-(1,3)-thioxolane-2-yl/-butanoic acid;

3-thia-4-/4-(4-acetamido-phenoxy)methyl-(Z,E)-(1,3)-thioxolane-2-yl/-butanoicacid;

2-acetylammino-4-thia-5-/4-(2-methoxyphenoxy)methyl-(Z,E)-(1,3)-thioxolane-2-yl/-pentanoic acid;

2-acetylammino-4-thia-5-/4-(4-methoxyphenoxy)methyl-(1,3)-thioxolane-2-yl/-pentanoic acid;

3-thia-4-/2-(2-methoxyphenoxy)methyl-(Z,E)(1,3)-dioxolane-4-yl/-butanoic acid;

methyl 2-(S)-acetylammino-4-thia-5-/2-(2-methoxyphenoxy)methyl-(Z,E)-(l,3)-dioxolane-4-yl/-pentanoate;

3-thia-5-(2-methoxyphenoxy)- pentanoic acid;

3-thia-5-(4-methoxyphenoxy)-pentanoic acid;

3-thia-5-(3,4,5-trimethoxyphenoxy)-pentanoic acid;

3-thia-5-(3,5-dimethoxy-4-hydroxy-phenoxy)-pentanoic acid;

3-thia-5-(3,5-ditert.butyl-4-hydroxy-phenoxy) pentanoic acid;

3-thia-5-(4-imidazol-i-yl-phenoxy)-pentanoic acid;

3-thia-5-(4-acetamido-phenoxy)-pentanoic acid;

3-thia-5-(2-methoxy-4-allyl-phenyl)-pentanoic acid;

1-(3-pyridyl-methylthio)methyl-4-(2-methoxyphenoxy)-methyl-(1,3)-dioxolane;

(Z,E)-2-(3-pyridyl-methylthio)-methyl-4(2-methoxyphenoxy)methyl-(l,3)-dioxolane;

(Z,E)-4-(3-pyridyl-methylthio)methyl-2(2-methoxyphenoxy)methyl-(1,3)-dioxolane;

(Z,E)-2-(3-pyridyl-methylthio)-methyl-4(methoxyphenoxy)methyl-(1,3)-dioxolane;

(Z,E)-2-(3-pyridyl-methylthio)-methyl-4-(2-methoxyphenoxy)-methyl-(1,3)-thioxolane:

1-(3-pyridyl)-2-thia-4(4-methoxyphenoxy)butane;

1-(3-pyridyl)-2-thia-4(-acetamido-phenoxy)butane;

1-(3-pyridyl)-2-thia-4-/4-(imidazol-1-yl)-phenoxy/butane;

1-(3-pyridyl)-2-thia-4-/2-methoxy-4-allyl-phenoxy/butane;

N-(3-pyridyl)-methy1,3-thia-4-/4-(2-methoxyphenoxy)-methyl-cis-trans-dioxolan-2-yl/-butanoicacid amide;

N-(3-pyridyl)methyl, 3-thia-5-(2-methoxyphenoxy) pentanoic acid amide;

N-(3-pyridyl)-3-thia-5-(4-methoxyphenoxy)-pentanoic acid amide:

N-(3-pyridyl)-3-thia-5-(3 4,5-trimethoxyphenoxy) pentanoic acid amide;

N-(3-pyridyl)methyl-3-thia-4-/4-(2-methoxyphenoxy)-methyl-(Z,E)-(1,3)-dioxolan-Z-yl/-butanoicacid amide;

N-(3-pyridyl)methyl-3-thia-4-/4-(4-methoxyphenoxy)methyl-(Z,E)-(1,3)-dioxolan-2-yl/-butanoic acid amide;

N-(3-pyridyl)methyl-3-thia-4-/2-(2-methoxyphenoxy)-methyl-(Z,E)-(1,3)-dioxolan-4-yl/-butanoicacid;

N-(3-pyridyl)methyl-3-thia-4-/4-(2-methoxyphenoxy)methyl-(Z,E)-(l,3)-dioxolan-4-yl/-butanoic acid amide;

N-(3-pyridyl)methyl-3-oxa-4-/4-(2-methoxyphenoxymethyl-(Z,E)-(1,3)-dioxolan-2-yl/butanoic acid amide.

The compounds of the invention of formula I are prepared by a process inwhich a compound of general formula II ##STR5## is reacted with acompound of general formula III ##STR6## wherein R, R₁, R₂, R₃, Ar, B,T, are as above defined and one of Z and W is OH or --SH while the otheris selected from the group of halogen, thioacetate, acetate, mesylate ortosylate. The reaction between a compound of formula II and a compoundof formula III is carried out reacting stoichiometrical amounts of thesereagents in a suitable solvent in presence of a stoichiometrical amountor a slight excess of a base. Suitable bases are alkaline or alkalineearth metals hydroxides, carbonates or alcoholates. Suitable solventsare methanol, ethanol, isopropanol, tert-butanol, water or theirmixtures.

Suitable bases can also be sodium or potassium hydrides in an inertsolvent, such as hydrocarbon, e.g. benzene, toluene, xylene, isooctane;an ether such as diethyl ether, diisopropyl ether, tert-butyl-ether,tetrahydrofuran, dioxane, dimethoxyethane or diglyme; dimethylformamideor dimethylsulphoxide.

The reaction is carried out at a temperature ranging from -20° C. to thesolvent's reflux temperature, or anyway, at temperatures not exceeding100° C. and the reaction time may range from one hour to some days. Whenin the compounds of formulae II and III one of W and Z is a free thiolgroup the reaction is carried out at room temperature in the presence ofa slight molar excess of sodium ethoxide, preferably in ethanol, andusually it is complete in 2 hours. When in the compounds of formulae IIand III one of W and Z is OH, the reaction is preferably carried out atroom temperature in an inert solvent, such as, for instance,dimethylformamide, in the presence of a slight molar excess of analkaline hydride such as, for instance, sodium hydride and it iscomplete in 3 hours.

Herebelow, for the sake of shortness, symbols used Previously forgeneral formulae will have the same meaning, unless otherwise indicatedin the context.

Compounds of general formula II can be prepared following known methods.Particularly, the preparation of compounds II wherein B is ##STR7## issummarized in the following scheme 1 ##STR8## wherein Z' is Cl, Br andZ" is OCOCH₃ or S--COCH₃ and Z'" is OH or SH.

The compounds IV, that are commercially available or preparableaccording to known methods, are reacted with a 10% molar excess of a3-halo-1,2-propandiol in the presence of a base such as potassium orsodium hydroxide in water or sodium ethoxide in ethanol, according to J.Org. Chem. (1950) 4986, for the preparation of diols of general formulaV.

The compounds of general formula VI wherein Z' is halogen, are preparedby reacting compounds V with a dimethyl- or diethylacetale of aα-halogen aldehyde in the absence of a solvent, at a temperature rangingfrom 50° C. to 150° C., in presence or not of catalytic amounts ofp-toluensulphonic or sulphosalicylic acid ranging from 10% molar to 25%molar with respect to the diol, or of a ion-exchange resin in acid form.

The reaction is carried out under a nitrogen atmosphere by heating amixture of diol V with the suitable α-halo- aldehyde acetale (in a molarexcess from 10% to 150%) removing by distillation the formed alcohol.Preferably 20% molar excess of α-chloro or α-bromo acetaldehyde dimethyl( or diethyl-) acetale, 10% molar excess of p-toluensulphonic acid isreacted with the diol of formula V, at a temperature of 80° C.,distilling off methanol or ethanol.

The compounds VI wherein Z' is iodine can be easily obtained bytreatment of a compound of formula VI wherein Z' is Cl, Br with anexcess of potassium iodide according to known methods.

The transformation of a compound of formula VI in a compound of formulaVII wherein Z" is CH₃ COS-- or CH₃ COO-- is carried out by treatment ofa compound of formula VI with an alkali acetate or thioacetate (in amolar excess from 100% to 300%). The reaction is carried out in an inertsolvent such as dimethylsulphoxide, dimethylformamide,dimethylacetamide, hexamethylphosphotriamide, acetone, acetonitrile orwater or their mixtures keeping the temperature in the range from 0° C.to 100° C., for a time from 1 hour to several days.

The halogen-acetate exchange is preferably carried out indimethylsulphoxide, at 70° C., with potassium acetate, in a 100% molarexcess, and the reaction is completed after 3 hours. Thehalogeno-thioacetate exchange preferably is carried out in acetone, forinstance, potassium thioacetate (300% excess) at room temperature, thereaction being usually complete after a night.

The compounds of general formula VIII wherein Z'" is OH or SH may beprepared, if desired, by hydrolysis of the corresponding acetates andthioacetates with aqueous concentrated solutions of ammonium hydroxide,in a water-miscible solvent such as dimethoxyethane, diglyme, triglyme,DMSO, THF, DMF, or their mixtures at room temperature in an inert gasatmosphere; the reaction time may range from a few minutes to some days.Preferred solvent is dimethoxymethane; the reaction has been usuallycompleted after 3 hours, at room temperature and under inert gasatmosphere.

The compounds of general formula I wherein B is a ##STR9## can beobtained in accordance with scheme 2 ##STR10## Oxidation with sodiumperiodate, in accordance with "Il Farmaco" Ed. Sc. 9, 156, (1956) of thediols V gives the aldehyde IX which can then be reacted withcommercially available 3-halo-1,2-propane diols X to give the dioxolanesXI.

The reaction of compounds X, wherein Z' is Cl or Br, with compounds IX(dioxolane XI formation) can be carried out by heating to the refluxtemperature a mixture of the aldehyde IX with a molar excess (from 10%to 50%) of the diol X , in an inert solvent such as benzene, toluene orxylene in presence of an acid catalyst, such as p-toluenesulphonic acid,sulphosalicylic acid or an ion-exchange resin in acid form byazeotropical removal of water in a time ranging from 1 to 12 hours. Thefollowing transformation of a compound of formula XI (Z'32 Cl or Br) ina compound of formula XII (Z'"=OH and SH) is performed according to theabove discussed procedure illustrating the conversion of a compound offormula VI in a compound of formula VIII.

The preparation of compounds of formula I wherein B is a single bond issummarized in scheme 3 ##STR11## wherein Z^(IV) is tosylate or mesylate,Z' is Br or Cl and Z^(V) is SCOCH₃ or SH.

The aldehydes of general formula IX can be reduced, if desired, bysodium borohydride, to the corresponding alcohols XIII, according toknown techniques.

The compounds XIII can then be transformed into the correspondingtosylates or mesylates of formula XIVa by reaction with a mesyl or tosylchloride in the presence of a tertiary amine such as triethylamine orpyridine. Said reactions are well known in chemical literature.Alternatively, alcohols XIII can be transformed into the correspondinghalides XIVc wherein Z' is chlorine or bromine by treatment respectivelywith thionyl chloride or with CBr₄ -tripheny lphosphine in accordancewith Synth. Comm. (1986)16, 1926.

As above mentioned for the preparation of compounds VIII, the compoundsXIVb wherein Z^(V) is SCOCH₃ can be obtained by reacting both compoundsXIVc and XIVa with potassium thioacetate. Thiols XIVb, wherein Z^(V) isSH, can then be obtained by subsequent treatment with ammonium hydroxidein an inert solvent such as water-miscible ethers.

The preparation of compounds I wherein B is ##STR12## is summarized inthe following scheme 4 ##STR13## The reaction between compounds IX andthe commercially available mercaptoalcohols XV, wherein Z' is Cl or Br,is carried out using reaction conditions similar to those abovedescribed in the reaction of compounds IX with diols X. 1,3-oxathiolanesXVIa, wherein Z' is Cl or Br, can then be transformed into thecorresponding acetates, thioacetates, alcohols and thiols XVIb, whereinZ^(VI) is OCOCH₃, SCOCH₃, OH or SH, according to the procedures abovedescribed in the dioxolanes XI series.

The compounds of general formula I wherein B is ##STR14## can also beprepared according to scheme 5 ##STR15## using known procedures;monotosylates XVII are obtained by selective monotosylation of theprimary hydroxy group of the diol V and are reacted with a 1:1 molarratio of potassium thioacetate and tetrabutyl ammonium bromide (in a300% molar excess in respect of the compounds XVII), at room temperaturein an inert solvent such as acetonitrile or acetone to give compoundsXVIII which are then transformed into thiols XIX by ammonolysis.Subsequent treatment of XIX with α-halo-acetaldehyde acetales affordsthe 1,3-thioxolanes XXa, wherein Z, is Cl or Br, whose halogen atom istransformed to give alcohols, acetates, thiols, thioacetates, mesylatesor p-toluensulphonates of formula XXb, wherein Z^(VII) is OCOCH₃, CH₃SO₃ --, CH₃ -C₆ H₄ --SO₃ --, --OH--SCOCH₃, SH, using the procedure abovedescribed in the case of preparation of dioxolanes VII and VIII.

To improve yields and to minimize consumption of basic reagents, theacetylation of the phenolic group, when one of R₁, R₂ or R₃ is hydroxymay be carried out, if desired, using known procedures, by treatmentwith acetyl chloride, then removing the acetate protecting group by mildhydrolysis with aqueous or ethanol solutions of sodium or potassiumhydroxides.

The compounds of formula III are commercially available or knownsubstances that are prepared using known methods. So, for example, thecompounds of formula III wherein T is 3-pyridyl, R is CH₂ and W ischlorine can be obtained by treating (3-pyridyl)methanol with SOCl₂ ;otherwise this latter compound may be reacted with mesyl chloride andthen with potassium thioacetate to give compounds of formula III whereinT is 3-pyridyl, R is CH₂ and W is thioacetate and/or thiol afterammonolysis.

The transformation of compounds of formula III wherein W is Cl, Br or Iinto the corresponding alcohols or thiols can be carried out using theprocedures for the Preparation of the compounds of general formula II.

The compounds of the general formula I wherein T is an ester or amidegroup may be obtained starting from a compound of formula I wherein T isCOOH by reaction with a suitable alcohol or amine using procedures wellknown in the art.

The compounds of the invention of general formula I are therapeuticallyuseful substances, devoid of toxic effects and conveniently used asbronchodilator, mucus-regulating and antitussive agents. Whenadministered by oral and intraperitoneal route to mice and rats (maleand female) they are devoid of acute toxic effects; LD₅₀ ranging from 1to 5 g/Kg are measured.

The compounds of the invention are particularly useful as antitussive,fluidifying of bronchial secretions and antiinflammatory agents.

The ability of a drug to modify the tracheo-bronchial mucus secretion isevaluated measuring the excretion of a dyestuff in the respiratory tree.

According to the procedure of M. Mawatari, Kagoshima Daigaken IgakenZasshi, 27, 561 (1976), Albino Swiss female mice are treated by oralroute with the drug and, 5 minutes after, with a 0.5 aqueous uraninesolution (0.1 ml/10 g body weight) by subcutaneous route. The animalsare sacrified 30 minutes after; the respiratory tree is excised andaccurately washed. The washing fluids (BAL) are collected and evaluatedfor the uranine content using a spectrofluorimetric technique.

Therapeutically active drugs such as bromexine and sobrerol are known toincrease the uranine content in the BAL's in a dose dependent way inrespect to the control values (BAL's of animal treated with vehicle).Red phenol is also used as dyestuff; according to the method of H.Hengler et al., (J. Pharm. Meth., 11, 151, 1984) the dyestuff isadministered as a 5% aqueous suspension intraperitoneally (500 mg/kg) 30minutes after oral treatment with the drug (or placebo). Albino Swissmale mice are used in this test and the animals are killed 30 minutesafter dye treatment. The dye content in BAL's is evaluatedspectrometrically at 546 nm.

An increased red phenol secretion in BAL's after drug treatment meansstimulation of mucus production.

In the following table, the pharmacological results, obtained withrepresentative examples of the compounds of the invention:

3-thia-5-(2-methoxy-phenoxy)-pentanoic acid (substance A);

N-(3-pyridyl)methy 1-3-thia-5 (2-methoxy-phenoxy)pentanoic acid amide(substance B);

3-thia-4-[4-(2-methoxy-phenoxy)methyl-(Z,E)-dioxolan-2-yl]-butanoic acid(substance C);

N-(3-pyridyl)methyl-3-thia-4-[4-(2-methoxy-phenoxy)-methyl-(Z,E)-(1,3)-dioxolan-2-yl]-butanoicacid amide substance D)

are reported and compared with those obtained with the above citedreference substances:bromexine (substance E) and sobrerol (substance F).

    __________________________________________________________________________    % INCREASE OF DYESTUFF SECRETION IN BAL                                       (vs. untreated animals)                                                       SUBSTANCE                                                                             RED PHENOL       URANINE                                              mg/kg os                                                                              A  B  C  D  E F  A  B  C  D  E F                                      __________________________________________________________________________     25     25 12 47  49                                                                              28                                                                              nt 45  70                                                                              25  66                                                                               0                                                                              nt                                      50     50 73 83 120                                                                              69                                                                              48 98 140                                                                              52 132                                                                              50                                                                               54                                    100     104                                                                              126                                                                              143                                                                              179                                                                              83                                                                              69 138                                                                              190                                                                              101                                                                              284                                                                              63                                                                              104                                    200     nt nt nt nt nt                                                                              111                                                                              nt nt nt nt nt                                                                              144                                    __________________________________________________________________________     nt = not tested                                                               E,F: reference substances                                                

The red phenol test is also useful for evaluating longlasting action ofthe investigated drugs. Infact, a substance can be administered 2, 1 and1/2 hours before the intraperitoneal administration of the red phenolmarker. If the animals are killed, as usual, half an hour after thedyestuff treatment, the overall time of drug action increases from 1 hrto 11/2 and 21/2 hrs respectively.

The results of this study, wherein full active fixed doses were used,are reported in the following table.

    ______________________________________                                        TIME-COURSE OF % INCREASE OF                                                  RED PHENOL EXCRETION                                                          (vs. untreated animals)                                                                             overall                                                               mg/kg   experiment hours                                        SUBSTANCE     (os)    1           11/2                                                                              21/2                                    ______________________________________                                        A             100     104        98   62                                      B             100     126        119  62                                      C             100     143        72   42                                      D             100     179        111  58                                      REFERENCE                                                                     SUBSTANCES                                                                    E             100      98        61   21                                      F             200     108        73   30                                      ______________________________________                                    

The above mentioned compounds of the invention (substances A-D) havebeen also tested as antitussive drugs. All the compounds possess a goodactivity; after oral administration (50 mg/kg) a 50% inhibition of cough(induced by aerosol of a 30% aqueous solution of citric acid) ismeasured.

They are useful for treatment of bronchial hyperreactivity that isthought to be partially a consequence of inflammatory conditions in thebroncho-trachealrespiratory tree.

Infiltration of eosinophiles, desquamation of wide areas of epithelium,mucus hypersecretion and bronchial smooth muscle hyperplasia are aspectsof these inflammatory events. In animal models, the compounds of theinvention are particularly able to prevent many of these experimentallyinduced events.

For example, the substance B (after e.v. treatment to anaesthetizedguinea-pigs submitted to a forced tobacco-smoking respiration, in therange of dosages from 5 to 30 mg/kg) is able to reduce the hyperreactivespasmus induced by acetylcholine challenge in dose dependent way.Positive reference substances in this novel experimental procedure arefor example 6-α-methylprednisolone and sodium dichromoglicate (i.m.administration).

For the above mentioned therapeutical uses, the compounds of theinvention are formulated in pharmaceutical compositions, usingconventional techniques and eccipients, as described in "Remington'sPharmaceutical Sciences' Handbook", Hack Publ. Co., New York, U.S.A.Examples of said compositions include capsules, tablets, packets,syrups, drinkable solutions, suppositories, vials for parenteral orinhalatory administration, controlled-release forms, etc.

Dosages will range from 100 and 2000 mg pro day as total amount and willbe administered in divided portions during the day, the specified dosagevarying depending on the age, weight and conditions of the patient, aswell as on the administration route; higher dosages even for longperiods have no contraindications.

The invention will be illustrated by the following non-limitingexamples.

EXAMPLE 1

A solution of 4-methoxyphenol (20 g) in absolute ethanol is slowly addedat room temperature to a solution of sodium ethoxide in ethanol (160 ml)prepared "in situ" dissolving 4.2 g of sodium under nitrogen atmosphere.

After 30' a solution of 3-chloro-propane-1,2-diol (14.7 ml) in absoluteethanol (20 ml) is added and the resulting solution is refluxed for 4hours. After cooling and removal of salts by filtration, the mixture isdried in vacuum and the residue is crystallized from diethylether. 29.8g of 3-(4-methoxy)phenoxy-propane-l.2-diol, m.p. 67°-69° C., areobtained.

EXAMPLE 2

Using a suitable phenol in the procedure of example 1, by reaction with3-chloro-propane-1,2-diol the following propane-1,2-diols are obtained:

3(2-hydroxy-phenoxy)-propane-1,2-diol;

3(3-4-5-trimethoxy-phenoxy)-propane-1,2-diol;

3(3-5-dimethoxy-4-hydroxy-phenoxy)-propane-1,2-diol;

3(3,5-ditert.butyl-4-hydroxy-phenoxy)-propane-1,2-diol;

3/4(imidazol-1-yl)-phenoxy/-propane-1,2-diol;

3(4-acetamido-phenoxy)propane-1,2-diol;

3/2-methoxy-4-allyl-phenoxy/-propane-1,2-diol.

EXAMPLE 3

3-(4-methoxy-phenoxy)-propane-1,2-diol (65.3 g) is added to a solutionof sodium periodate (60.5 g) in water (600 ml), cooled at 0°, and theresulting suspension has been stirred at 0° C. for two hours. Afteraddition of ethyl acetate (1l) the organic phase is separated, washedwith water, dried on sodium sulphate. Removal of the solvent undervacuum affords 2(4-methoxy-phenoxy)ethanale (45 g) as a clear oil.

IR: γ1725 cm⁻¹ (γ=CO); 835 cm⁻¹ (δCH are OUT, adjacent 2H); NMR (CDCl₃)δ=3,8 3H (s) OCH₃ ; δ=4,5 2H (s) --CH₂ --CHO--; δ=9,8, 1H (s) CHO.

EXAMPLE 4

Using a suitable 3-substituted-propane-1,2-diol of the example 2 in theprocedure of example 3, the following 2-substituted ethanales areobtained:

2(2-methoxyphenoxy)ethanale (m.p. 65°-67° C.);

2(3,4,5-trimethoxyphenoxy)ethanale;

2/4-(imidazol-1-yl)phenoxy/-ethanale;

2-/2-methoxy-4-allyl-phenoxy/-ethanale.

EXAMPLE 5

Sodium borohydride (3.78 g) is added to a solution of2(2-methoxyphenoxy)ethanale (16.6 g) in methanol (20 ml) cooled at 0°C., in small portions, keeping the temperature under 10° C. After 30' at10° C. the reaction mixture is poured in aqueous NaH₂ PO₄ 30% (200 ml)and extracted with ethyl acetate (3×100 ml). The organic extracts arewashed with water, dried on Na₂ SO₄ and concent rated under vacuum togive 2-(2-methoxy)-ethanol (13.5 g) as a yellow oil (NMR(CDCl₃)=2,8,3,7, 1H (m) OH disappears with D₂ O;

IR:=3000-3600 cm⁻¹ (OH). A solution of 5 g of the above product indichlooroethane (40 ml), cooled at 0° C., is treated with triethylamine(4.6 ml) and with a solution of methanesulphonyl chloride (2.55 ml) indichloroethane which is then added dropwise. The reaction mixture isstirred for 3 hours at room temperature and then filtered.

The filtrate is washed with water, 5% aqueous NaHCO₃ and again withwater. After anhydrification on sodium sulphate and removal of thesolvent under vacuum the residue is crystallized from isopropyl ether togive 5.4 g of 2-(2-methoxyphenoxy)-ethyl methanesulphonate, m.p. 73°-76°C.

EXAMPLE 6

After reduction of a suitable 2-substituted ethanale of the examples 3and 4 with NaBH₄ and after reaction with methane sulphonyl chloride,according to example 5, the following methanesulphonates are obtained:

2-/2-methoxy-4-allyl-phenoxy /-ethyl methanesulphonate;

2(4-methoxyphenoxy)ethyl methanesulphonate;

2-(4-imidazol-1-yl-phenoxy)ethyl methanesulphonate;

2-(4-acetamidophenoxy)ethyl methanesulphonate.

EXAMPLE 7

A solution of 3-(2-methoxy-phenoxy)-propane-1,2-diol (4.7 g) inpyridine, cooled at 5°-10° C., is treated under stirring with a solutionof p-toluensulphonylchloride (4.5 g) in benzene (70 ml). The reactionmixture is stirred overnight at room temperature, then it is washed with2N HCl (3×100 ml) and with water, dried on Na₂ SO₄ and evaporated todryness in vacuum. The oily residue is purified by column chromatography(silica gel--230-400 mesh hexane/AcOEt=3/1) to yield 5 g of3-(2-methoxy-phenoxy)-2-hydroxy-1-propyl.

p-toluensulphonate (oil. NMR (--CDCl₃): δ=2,4 3H (s) CH₃ SO₂ ;δ=3.75-4.4 5H (m) OCH₃ +OCH₂.

Potassium thioacetate (2 g) and tetrabutylammonium bromide (0.7 g) areadded to a solution of 4 g of this compound in acetonitrile (50 ml) andthe mixture is refluxed for 3 hours. After evaporation to dryness, theresidue is partitioned between water and ethyl acetate and the organicphase is evaporated to dryness. A solution of the residual oil (2.5 g of3(2-methoxyphenoxy)-1-acetylmercapto-(propane-2-ol) in dimethoxyethane(50 ml) is treated with 28% aqueous ammonium hydroxide (10 ml); themixture is kept for 3 hours at room temperature and then it isevaporated under vacuum. The oily residue is purified by columnchromatography (silica gel--230-400 mesh--AcOEt) to give 1.7 g of3-(2-methoxy-phenoxy)-1-mercapto-propan-2-ol.

EXAMPLE 8

Using in the procedure of example 7 a suitable3-(aryloxysubstituted)-1,2-propane-diol of examples and 2, the followingcompounds are obtained:

3(4-methoxy-phenoxy)-1-mercapto-propane-2-ol;

3(3,4,5-trimethoxy-phenoxy)-1-mercapto-propane-2-ol;

3/4-(imidazol-1-yl)phenoxy/-1-mercapto-propane-2-ol;

3(4-acetamido-phenoxy)-1-mercapto-propane-2-ol.

EXAMPLE 9

A stirred mixture of 3-(2-methoxy-phenoxy)-propane-1,2-diol (100 g),sulphosalicylic acid (3 g) and 2-bromo-ethanaldiethylacetal is heatedfor 4 hours at 100° C., distilling off ethanol. After cooling, thereaction mixture is diluted with ethyl acetate (100 ml), washed with 5%aqueous NaHCO₃ and water; after drying on Na₂ SO₄ the solvent isevaporated in vacuum. The residue is crystallized from diisopropyl etherto afford 15.4 g of(Z,E)-2-bromomethyl-(2-ethoxy-phenoxy)methyl-(1,3)-dioxolane, m.p.45°-53° C. A solution of this compound (10 g) in CCl₄ (25 ml) isadsorbed on a silica gel column (400 g) and eluted with AcOEt/petroleumether (1:1) to give 4 g of(E)-2-bromomethyl-4-(2-methoxy-phenoxy)-methyl-1,3-dioxolane, m.p.52°-53° C. and

4 g of (Z)-2-bromomethyl-4-(2-methoxy-phenoxy)methyl-1,3-dioxolane, m.p.60°-61° C. (after crystallization from EtOH).

EXAMPLE 10

Using in the procedure of example 9 a suitable3-substituted-1,2-propandiol, the following compounds are obtained:

(Z,E)-4-(2-hydroxy-phenoxy)methyl-2-bromomethyl-(1,3)-dioxolane;

(Z,E)-4-(3,4,5-trimethoxyphenoxy)methyl-2-bromomethyl-(1,3)-dioxolane;

(Z,E)-4-(3,5-dimethoxy-4-hydroxy-phenoxy)methyl-2-bromomethyl-(1,3)-dioxolane;

(Z,E)-4-(3,5-ditert.butyl-4-hydroxy-phenoxy)-methyl-2-bromomethyl-(1,3)-dioxolane;

(Z,E)-4-/4-(imidazol-1-yl)phenoxy/-methyl-2-bromomethyl(1,3)-dioxolane;

(Z,E)-4-(4-acetamidophenoxy)methyl-2-bromomethyl-(1,3)-dioxolane;

(Z,E)-4-/2-methoxy-4-allyl-phenoxy/-methyl-2-bromomethyl-(1,3)-dioxolane;

(Z,E)-4-(4-methoxyphenoxy)methyl-2-bromomethyl (1,3)-dioxolane.

EXAMPLE 11

A stirred suspension of potassium acetate (13.5 g) and of(Z,E)-2-bromomethyl-4-(4-methoxy-phenoxy)-methyl-1,3-dioxolane (20 g) indimethylsulphoxide (100 ml) is heated for 2 hours at 100° C. Aftercooling the reaction mixture is poured in iced water (250 ml) andextracted with diethylether. After anidrification on Na₂ SO₄ and solventremoval, the purification of the crude residue by column chromatography(silica gel 30-100 mesh, eluent: hexane/AcOEt=3:1) yields 15 g of(Z,E)-2-acetoxymethyl-4-(4-methoxyphenoxy)-methyl-(1,3)-dioxolane as aclear oil.

IR=1735 cm⁻¹ (γ C═O), γ=1240 cm⁻¹ (C--O as,sim) γ=1100 cm⁻¹ (γ asC--O--C alicyclic ethers); NMR (CDCl₃): δ=2.34 3H (s) CH₃ CO.

A solution of this compound in dimethylsulhpoxide is treated with asolution of potassium carbonate (17 g) in water (60 ml) and heated for 3hours at 50° C. The aqueous solution is saturated with NaCl andextracted with ethyl acetate. The extracts are dried, decolourized withcharcoal and evaporated to dryness under vacuum to give aftertrituration with diisopropylether 12 g of(Z,E)-2-hydroxymethyl-4-(4-methoxyphenoxy)methyl-1,3-dioxolane, m.p.44°-49° C.

EXAMPLE 12

A suitable 4-substituted-2-halomethyl-(1,3)-dioxolane of examples 9 and10 is reacted according to the example 11 and the following compoundsare obtained:

(E)-4-(2-methoxyphenoxy)methyl-2-hydroxymethyl-(1,3)-dioxolane, m.p.68°-69° C.;

(Z)-4-(2-methoxyphenoxy)methyl-2-hydroxymethyl (1,3)-dioxolane,m.p.57°-59° C.;

(Z,E)-4-(4-methoxyphenoxy)methyl-2-hydroxymethyl (1,3)-dioxolane;

(Z,E)-4-(3,4,5-trimethoxyphenoxy)methyl-2-hydroxymethyl-(1,3)-dioxolane;

(Z,E)-4-(3,5-dimethoxy-4-hydroxy-phenoxy)methyl-2-hydroxymethyl-(1,3)-dioxolane;

(Z,E)-3-(3,5-ditert.butyl-4-hydroxy-phenoxy)methyl-2-hydroxymethyl-(1,3)-dioxolane;

(Z,E)-4-(4-acetamidophenoxy)methyl-2-hydroxymethyl (1,3)-dioxolane;

(Z,E)-4-/(imidazol-1-yl)phenoxy/methyl-2-hydroxymethyl-(1,3)-dioxolane;

(Z,E)-3-/2-methoxy-4-allyl-phenoxy/-methyl (1,3)-dioxolane.

EXAMPLE 13

A stirred suspension of(Z,E)-2-(2-methoxyphenoxy)-methyl-4-bromomethyl-1,3-dioxolane (6.84 g)and potassium thioacetate (6.08 g) in acetonitrile (300 ml) is refluxedfor 5 hours under inert gas atmosphere.

The solvent is concentrated to a small volume and the residual mixtureis poured into iced water.

The aqueous phase is extracted with ethyl aceate to give after the usualwork-up an oily residue which is purified by column chromatography(silica gel--230-400 mesh--hexane/ethyl acetate=1:1) so yielding 3 g of(Z,E)-2-(2-methoxyphenoxy)-methyl-4-acetylthiomethyl(1,3)-dioxolane as alimpid oil, (IR=γ 1690 cm⁻¹ (C═O of RCOSR) NMR (CDCl₃): δ=2.3 3H (s) CH₃--COS--; δ=3.1-2.9 2H (d) CH₂ --S--; δ=5.2 1H (t)--O--CH--O--).

A solution of 2 g of this compound in dimethoxyethane (15 ml) is treatedwith concentrated ammonium hydroxide (5 ml) at room temperature, undernitrogen. After 24 hours the reaction mixture is concentrated to drynessunder vacuum and the residue is diluted with ethyl acetate. The organicphase is washed with water (2×5 ml), dried on Na₂ SO₄ and concentratedto dryness. The residue is purified by column chromatography (silicagel--230-400 mesh--hexane/ethyl acetate=1:2) and 0.7 g of2-(Z,E)-2-methoxyphenoxy)-methyl-4-mercaptomethyl-(1,3)-dioxolane areobtained as uncoloured oil (IR=γ 2250 cm⁻¹, (SH) NMR (CDCl₃) δ=3-3.15 2Hdd--CHS--.

EXAMPLE 14

Using in the procedure of example 12 a suitable 2-halo-methyl-dioxolaneof the examples 9 and 10, the following compounds are obtained:

(Z,E)-2-acetylthiomethyl-4-(4-methoxy-phenoxy) methyl-(1,3)-dioxolane;

(Z,E)-2-mercaptomethyl-4-(4-methoxy-phenoxy)methyl (1,3)-dioxolane;

(Z,E)-2-acetylthiomethyl-4-(3,4,5-trimethoxyphenoxy)methyl-(1,3)-dioxolane.

EXAMPLE 15

A solution of (E)-2-hydroxymethyl-4-(2-methoxyphenoxy)methyl-1,3-dioxolane in dimethylformamide (DMF) is added under nitrogenatmosphere to a suspension of sodium hydride (80% in mineral oil, 0.57g). The mixture is warmed at 40° C. for 30', and then cooled at 0°-10°C., slowly added dropwise thereto a solution of ethyl bromoacetate (2.12ml) in DMF. After 12 hours at room temperature, the reaction mixture isdiluted with aqueous NaH₂ PO₄ (100 ml) and extracted with ethyl acetate.After washing with water (3×30 ml) the organic phase is dried on Na₂ SO₄and evaporated under vacuum to give 2.7 g of ethyl4-/(E)-4-(2-methoxy-phenoxy)methyl-(1,3)-dioxolane-2-yl/-3-oxa-butanoateas a clear oil (NMR CDCl₃):

δ=1,2,3H (t) CH₃ --CH₂ --O; δ=3,6, 2H (d)--CH₂ --O--CH₂ COOEt, δ=3,8, 3H(s) CH₃ --O--, δ=6,8 4H (s) CH aromatic).

A suspension of this compound in aqueous NaOH N (20 ml) is stirred for 3hours at room temperature to obtain a clear solution which is thenextracted with ethyl acetate (2×10 ml) and the organic phase isdiscarded. The aqueous phase is acidified to pH 2.5-3 by treatment witha 10% aqueous KHSO₄ solution and extracted with ethyl acetate (5×10 ml).These organic extracts are collected, washed with water (2×10 ml) driedon Na₂ SO₄ and concentrated to dryness under vacuum. The residuecrystallizes from diisopropyl ether affording 2.0 g of3-oxa-4-/4-(2-methoxy-phenoxy)methyl-(E) (1,3)-dioxolane-2-yl/butanoicacid; m.p.86°-88° C.

In a similar way and starting from(Z)-4-/(2-methoxy-phenoxy)-methyl/-2-bromo-methyl (1,3)-dioxolane andfrom a (1:1) mixture of the Z and E isomers, the following compounds areobtained respectively:

3-oxa-4-/4-(2-methoxyphenoxy)methyl-(Z)-(1,3) dioxolan-2-yl/butanoicacid, m.p. 64°-66° C. and

3-oxa-4-/(2-methoxyphenoxy)methyl-(Z,E)-(1,3)-dioxolan-2-yl/butanoicacid, m.p. 68°-69° C.

EXAMPLE 16

Using in the procedure of example 14 a suitable4-substituted-2-bromomethyl-dioxolane of the examples 9 and 10, thefollowing compounds are obtained:

3-oxa-4-/4-(3,5-ditert.butyl-4-hydroxyphenoxy)methyl(Z,E)-(1,3)-dioxolan-2-yl/-butanoic acid;

3-oxa-4-/4-(3,5-dimethoxy-4-hydroxyphenoxy)methyl(Z,E)-(1,3)-dioxolan-2-yl/-butanoic acid;

3-oxa-4-/4-(3.4,5-trimethoxyphenoxy)methyl(Z,E)-(1,3)-dioxolan-2-yl/-butanoic acid;

3-oxa-4/4-(2-methoxy-4-allyl-phenoxy)methyl-(Z,E)(1,3)-dioxolan-2-yl/butanoicacid;

3-oxa-4-/4-(4-methoxy-phenoxy)methyl-(Z,E)-(1,3) dioxolan-2-yl/-butanoicacid.

EXAMPLE 17

A solution of methyl thioglycolate (1.62 ml) in methanol (5 ml) is addeddropwise under an inert gas atmosphere to a stirred solution of sodiummethoxide (from 0.46 g of Na) in methanol (40 ml); after 30 minutes 5 gof (Z,E)-2-brono-methyl-4-(2-methoxyphenoxy)methyl-1,3-dioxolane areadded dropwise to the mixture.

The mixture is refluxed for 2 hours, diluted with aqueous 2N NaOH (8.5ml) and heated again for 2 hours at the reflux temperature.

After concentration to a small volume the mixture is diluted with water(20 ml) and washed with ethyl acetate and these extracts are discarded.The aqueous phase is then acidified to pH 2.5 (H₂ SO₄ 2N) and extractedwith ethyl acetate (3×20 ml). The combined extracts are dried on Na₂SO₄, evaporated to dryness under vacuum to yield 3.2 g of3-thia-4-/4-(2-methoxy-phenoxy)-methyl-(Z,E)-(1,3)-dioxolan-2-yl/-butanoicacid (m.p. 62°-67° C.). Using in the same procedure, pure (Z) or(E)-2-bromomethyl-dioxolanes the following pure geometrical isomers3-thia-4-/4-(2-methoxyphenoxy)methyl-(Z)-(1,3)- dioxolan-2-yl/butanoicacid (m.p. 82°84° C.) and3-thia-4-/4-/2-methoxyphenoxy)methyl-(E)-(1,3-dioxolan-2-yl/-butanoicacid (m.p. 78°-82° C.), are obtained.

EXAMPLE 18

Using in the procedure of example 17 a suitable 4-substituted2-halomethyl-dioxolane of the examples 9 and 10, the following compoundsare obtained:

3-thia-4-/4-(4-methoxy-phenoxy)methyl-(Z,E)-(1,3)dioxolane-2-yl/butanoicacid;

3-thia-4-/4-(2-hydroxy-phenoxy)methyl-(Z,E)-(1,3)dioxolane-2-yl/-butanoic acid;

3-thia-4-/4-(3,4,5-trimethoxy-phenoxy)methyl-(Z,E)(1,3)-dioxolane-2-yl/-butanoic acid;

3-thia-4-/4-(3,5-dimethoxy-4-hydroxy-phenoxy)methyl(Z,E)-(1,3)-dioxolan-2-yl/butanoic acid;

3-thia-4-/4-(4-imidazol-1-yl-phenoxy)methyl-(Z,E)(1,3)-dioxolane-2-yl/-butanoic acid;

3-thia-4-/4-(3,5-ditert.butyl-4-hydroxy-phenoxy)methyl(Z,E)-(1,3)-dioxolane-2-yl/-butanoic acid;

3-thia-4-/4-(4-acetamido-phenoxy)methyl-(Z,E)(1,3)-dioxolane-2-yl/-butanoic acid;

3-thia-4-/4-(2-methoxy-4-allyl-phenoxy)methyl-(Z,E)(1,3)-dioxolane-2-yl/butanoic acid.

EXAMPLE 19

Using N-acetyl-L-cysteine methylester and2-(S)-mercapto-propionylglycine ethylester instead ofmethylthioglycolate in the procedure of example 17 and by reaction witha suitable 2-halo-methyl-dioxolane of examples 9 and 10, the followingcompounds are obtained:

2-(acetylamino)-4-thia-5-/4-(2-methoxyphenoxy)methyl(Z,E)-(1,3)-dioxolane-2-yl/-pentanoicacid;

2-(acetylamino)-4-thia-5/4-(4-methoxy-phenoxy)-methyl-(Z,E)-(1,3)-dioxolane-2-yl/-pentanoicacid;

(2S)-2-methyl-3-thia-4-/4-(2-methoxy-phenoxy)methyl(Z,E)-(1,3)-dioxolane-2-yl/-butanoylglycine;

(2S)-2-methyl-3-thia-4-/4-(4-methoxy-phenoxy)methyl(Z,E)-(1,3)-dioxolan-2-yl/-butanoyl glycine.

EXAMPLE 20

Using in the procedure of example 9 a3-substituted-propane-1-mercapto-2-ol of examples 7 and 8 instead of the3-substituted propane-1,2-diol by reaction with 2-bromo-ethanol diethylacetal in presence of sulfosalicylic acid, the following(1,3)-thioxolanes are obtained:

(Z,E)-4-(2-methoxy-phenoxy)methyl-2-bromomethyl-(1, 3)thioxolane;

(Z,E)-4-(4-methoxy-phenoxy)methyl-2-bromomethyl (1,3)-thioxolane;

(Z,E)-4-(3,4,5-trimethoxy-phenoxy)methyl-2-bromomethyl-(1,3)-thioxolane;

(Z,E)-4-(4-imidazol-1-yl-phenoxy)methyl-2-bromomethyl-(1,3)-thioxolane;

(Z,E)-4-(4-acetamido-phenoxy)methyl-2-bromomethyl (1,3)-thioxolane.

EXAMPLE 21

By reaction of a 2-halomethyl-(1,3)-thioxolane of example 20 with ethylthioglycolate, N-acetylcysteine methylester or2S-mercaptopriopionylglycine, according to the examples 17 and 19, thefollowing compounds are obtained:

3-thia-4-/4-(2-methoxy-phenoxy)methyl-(Z,E)(1,3)-thioxolane-2-yl/-butanoicacid;

3-thia-4-/4-(4-methoxy-phenoxy)methyl-(1,3)-thioxolan-2-yl/-butanoicacid;

3-thia-4-/4-(3,4,5-trimethoxy-phenoxy)methyl-(Z,E)-(1,3)-thioxolan-2-yl/-butanoicacid;

3-thia-4-/4-(4-imidazol-1-yl-phenoxy)methyl-(Z,E)-(1,3)-thioxolan-2-yl/-butanoicacid;

3-thia-4-/4-(4-acetamido-phenoxy)methyl-(Z,E)-(1,3)-thioxolan-2-yl/-butanoicacid;

2-(acetylamino)-4-thia-5/4-(2-methoxy-phenoxy)-methyl-(Z,E)-(1,3)-thioxolan-2-yl/-pentanoicacid;

2-acetylamino-4-thia-5-/4-(4-methoxy-phenoxy)methyl(1,3)-thioxolan-2-yl/pentanoic acid;

(2S)-2-methyl-3-thia-4-/4-(2-methoxy-phenoxy)methyl(Z,E)-(1,3)-thioxolane-2-yl/-butanoyl-glycine.

EXAMPLE 22

A solution of 2-(2-methoxy-phenoxy)ethanale (48 g)3-bromo-1,2-propandiol (52,7 g) and p-toluensulphonic acid (3.85 g) inbenzene (500 ml) is refluxed for 5 hours with azeotropic removal of thewater formed during the reaction.

Potassium carbonate (20 g) is added to the cooled solution, thesuspension is stirred overnight, filtered and the filtrate is evaporatedto dryness in vacuum to give an oily residue which is distilled in highvacuum (m.p. 178°-185° C. 0.5 mm Hg) to obtain 33.4 9 of(Z,E)-2-(2-methoxyphenoxy)-4-bromomethyl-1,3-dioxolane.

EXAMPLE 23

Using in the procedure of example 22 a suitable 2-substituted ethanaleof examples 3 and 4, the following compounds are obtained:

(Z,E)-2-(4-methoxy-phenoxy)methyl-4-bromomethyl-(1,3)-dioxolane;

(Z,E)-2-(3,4,5-trimethoxyphenoxy)methyl-4-bromomethyl 1,3)-dioxolane;

(Z,E)-2-(4-imidazol-1-yl-phenoxy)methyl-4-bromomethyl (1,3)-dioxolane;

(Z,E)-2-(2-methoxy-4-allyl-phenoxy)-methyl-4-bromomethyl-(1,3)-dioxolane.

EXAMPLE 24

By reaction of a(Z,E)-2-(2-methoxy-phenoxy)-methyl-4-bromomethyl-1,3-dioxolane ofexamples 22 and 23 with potassium acetate, according to the example 11,or with potassium thioacetate, according to the example 13, orrespectively with methyl thioglycolate or N-acetylcysteine methylester,according to the examples 17 and 19, the following compounds areobtained:

(Z,E)-2-(2-methoxy-phenoxy)methyl-4-acetoxymethyldioxolane;

(Z,E)-2-(2-methoxy-phenoxy)methyl-4-hydroxymethyldioxolane;

(Z,E)-2-(2-methoxy-phenoxy)methyl-4-acetylthiomethyl dioxolane;

(Z,E)-2-(2-methoxy-phenoxy)methyl-4-mercaptomethyl dioxolane;

3-thia-4-/2-(2-methoxy-phenoxy)methyl-(Z,E)-(1,3)-dioxolan-4-yl/-butanoicacid;

2-(acetylamino)-4-thia-5-/2-(2-methoxy-phenoxy)methyl(Z,E)-(1,3)-dioxolan-4-yl/-pentanoic acid (m.p. 80°-82° C.).

EXAMPLE 25

By reaction of a methanesulphonate of examples 5 and 6 with a methylthioglycolate, according to the example 17, the following compounds areobtained:

3-thia-5-(2-methoxy-phenoxy)-pentanoic acid, m.p. 69°-71° C.;

3-thia-5-(4-methoxy-phenoxy)pentanoic acid;

3-thia-5-(3,4,5-trimethoxy-phenoxy)pentanoic acid;

3-thia-5-(3,5-dimethoxy-4-hydroxy-phenoxy)pentanoic acid;

3-thia-5-(4-imidazol-1-yl-phenoxy)pentanoic acid;

3-thia-5-(4-acetamido-phenoxy)pentanoic acid;

3-thia-5-(2-methoxy-4-allyl-phenoxy)-pentanoic acid.

EXAMPLE 26

Methanesulphonylchloride (31.7 ml) is slowly added dropwise to a stirredsolution of (3-pyridyl)-methanol (39.6 ml) and triethylamine (55.7 ml)in dichloroethane (600 ml), cooled at 0° C.

The reaction mixture is left for 40 minutes at 0° C. and filtered. Theorganic filtrate is washed with water (2×100 ml) and then it is treatedwith a solution of potassium thioacetate (48 g ) in water (250 ml) for 2hours under vigorous stirring.

The separated organic phase is washed with water (2×100 ml), dried onNa₂ SO₄ and evaporated to dryness in vacuum to give an oily residue ofcrude 3-(acetylthiomethyl)pyridine (48 g).

A solution of potassium carbonate (1.4 g) in water (5 ml) and2-(2-methoxy-phenoxy)ethyl-methane sulphonate (1.05 g) are added to asolution of crude 3-(acetylthiomethyl)-pyridine (0.7 g) in ethanol (20ml); the stirred mixture is heated for 2 hours at 50° C.

The mixture is cooled, diluted with water and extracted with ethylacetate (2×20 ml). The collected organic extracts are washed with water(3×10 ml), dried and evaporated to dryness in vacuum. The oily residueis purified by column chromatography (silica gel--230--400 mesh--AcOEt)to give 1 g of 1-(3-pyridyl)-2-thia-4-(2-methoxy-phenoxy) butane as aclear oil.

NMR (CDCl₃): δ=2,75,2H (t) CH₂ --S--; δ3.8-3.85,3+2H (2s)--OCH₃+S--CH_(--Py;) δ= 4.15 2H (t) --CH₂ --O--; δ=6.8 4H (s)phenyl; 7-8.7 4H(m)-pyridyl.

EXAMPLE 27

By reaction of a suitable halomethyl-(1,3)-dioxolane of examples 9, 10,22 and 23 or of a suitable halomethyl-(1,3)-thioxolane of example 20and/or suitable methanesulphonates of the examples 5 and 6 with a(acylthiomethyl)pyridine prepared according to example 26 , thefollowing compounds are obtained:

(Z,E)-2-(3-pyridyl-methylthio)methyl-4-(2-methoxyphenoxy)-methyl-(1,3)-dioxolane;

(Z,E)-4-(3-pyridyl-methylthio)methyl-2-(2-methoxyphenoxy)-methyl-(1,3)-dioxolane;

(Z,E)-2-(3-pyridyl-methylthio)methyl-4-(4-methoxyphenoxy)methyl-(1,3)-dioxolane;

(Z,E)-2-(3-pyridyl-methylthio)methyl-4-(2-methoxyphenoxy)-methyl-(1,3)-thioxolane;

1-(3-pyridyl)-2-thia-4-(4-methoxy-phenoxy)butane;

1-(3-pyridyl)-2-thia-4-(4-acetamido-phenoxy)-butane;

1-(3-pyridyl)-2-thia-4-(4-imidazol-1-yl-phenoxy)butane;

1-(3-pyridyl)-2-thia-4-(2-methoxy-4-allyl-phenoxy)-butane.

EXAMPLE 28

A solution of dicyclohexylcarbodiimide (2.5 g) in DMF (10 ml) is slowlyadded dropwise to a solution of3-thia-4-/4-(2-methoxy-phenoxy)methyl-(Z,E)-(1,3)-dioxolan-2-yl/-butanoicacid (3.4 g) and 3-aminomethyl-pyridine (1.08 g) in dimethylformamide(10 ml), cooled at 0° C.

After 30' at 0° C., the reaction temperature is raised up to roomtemperature. After 4 hours the mixture is filtered and concentrated todryness under vacuum; the residue is purified on silica gel column(EtOAc/MeOH=10:1) affording 2.5 g ofN-(3-pyridyl)-methyl-3-thia-4-/4-(2-methoxyphenoxy)methyl-(Z,E)-(1,3)-dioxolan-2-yl/-butanoicacid amide.

EXAMPLE 29

By reacting according to example 26 the appropriate carboxylic acidswith 3-aminomethyl-pyridine, the following compounds are obtained:

N-(3-pyridyl)methyl-3-thia-5-(2-methoxy-phenoxy) pentanoic acid amide;

N-(3-pyridyl)methyl-3-thia-5-(4-methoxy-phenoxy) pentanoic acid amide;

N-(3-pyridyl)methyl-3-thia-5-(3,4,5-trimethoxy-phenoxy pentanoic acidamide;

N-(3-pyridyl)methyl-3-thia-4-/4-(2-methoxy-phenoxy)methyl-(Z,E)-(1,3)-dioxolan-2-yl/-butanoicacid amide;

N-(3-pyridyl)methyl-3-thia-4-/4-(4-methoxy-phenoxy)methyl-(Z,E)-(1,3)-dioxolan-2-yl/-butanoic acid amide;

N-(3-pyridyl)methyl-3-thia-4-/2-(2-methoxy-phenoxy)methyl-(Z,E)-(1,3)-dioxolan-3-yl/-butanoic acid amide;

N-(3-pyridyl)methyl-3-oxa-4-/4-(2-methoxy-phenoxy)methyl-(Z,E)-(1,3)-dioxolan-2-yl/-butanoic acid amide.

We claim:
 1. Compounds of formula I ##STR16## wherein: Ar is phenyl;R₁,R₂ and R₃ are substituents of the phenyl group Ar in 2-, 3-, 4- and5-position and which can be the same or different and are selected fromthe group consisting of hydrogen, hydroxy, (C₁ -C₅)-acyloxy, (C₁-C₄)-alkyl, (C₁ -C₄)-alkoxyl, (C₂ -C₄)-alkenyl, halogen, (C₁-C₅)-acylamino, phenyl, phenoxy, carboxyl, (C₁ -C₃)-alkoxycarbonyl,carboxy-(C₁ -C₄)-alkyl; B is 1, 3-dioxolan-diyl radical: X is sulphur oroxygen; R represents a --(CH₂)_(n), --CH(R₄)--, a --CH₂ --CH(NH₂)-- or--CH₂ --CH(NH--CORa)-group; T is carboxyl, --CO₂ R₆, --COR₆, --CO₂ NH₂,--CONRdRe, --CO--NH--CH(Rc)--CO₂ Ra or a di-(C₁ -C₄)-alkylamino-(C₁-C₄)-alkylaminocarbonyl, hydroxy-(C₁ -C₄)-alkoxy-(C₁ -C₄)-alkoxy-(C₁-C₄)-alkylaminocarbonyl, or di-(C₁ -C₄)-alkyl-amino-(C₁ -C₄)-alkoxy-(C₁-C₄)-alkyl-amino-carbonyl group; n is 1 or 2; R₄ represents a (C₁-C₄)-alkyl or a (C₂ -C₄)alkenyl group; R₆ is a (C₁ -C₆)-alkyl groupoptionally substituted by (C₁ -C₆)-alkyl group optionally substituted by(C₁ -C₆)-alkoxyl, carboxyl, (C₁ -C₄)-alkylamino, di-(C₁ -C₄)-alkylamino,(C₃ -C₆)-alkenyl, phenyl, or phenyl-(C₁ -C₆)-alkyl groups; Ra ishydrogen or a C₁ -C₄)-alkyl group and Rc is hydrogen or a (C₁-C₆)-alkyl, or pyridyl or (C₆ -C₁₄)-ar-(C₁ -C₄)-alkyl, Rd and Re, whichcan be the same or difference, are hydrogen, a (C₁ -C₆)-alkyl group,optionally substituted by a (C₁ -C₆)-alkoxy, hydroxy-(C₁ -C₄)-alkoxy-(C₁-C₄)-alkyl or di-(C₁ -C₄)-alkyl-amino-(C₁ -C₄)-alkyl-amino-(C₁-C₄)-alkoxy-(C₁ -C₄)-alkyl group, or Rd and Re together with thenitrogen atom to which they are bonded form a pyridyl heterocyclic ring,as well as their enantiomers or diastereomers and the pharmaceuticallyacceptable salts thereof.
 2. Compounds according to claim 1 wherein X isoxygen.
 3. Compounds according to claim 1 wherein X is sulphur. 4.Compounds according to claim 1, 2 or 3 wherein B is a1,3-dioxolan-2,4-diyl or 1,3-dioxolan-4,2-diyl.
 5. Compounds accordingto claim 1, 2 or 3 wherein T is carboxyl, (C₁ -C₃)-alkoxycarbonyl,carboxyamide, --CONRdRe, (3-pyridyl)methylaminocarbonyl, or--CO--NH--CH(Rc)--CO₂ Ra.
 6. Compounds according to claim 1, 2 or 3wherein R₁, R₂ and R₃ are hydrogen, hydroxy, (C₁ -C₄)-alkyl, (C₁-C₄)-alkoxy, (C₂ -C₄)-alkenyl, halogen, or (C₁ -C₅)-acylamino.
 7. Apharmaceutical composition containing a compound according to any one ofclaims 1, 2 or 3, and a pharmaceutically acceptable carrier or adjuvant.8. A method of producing a mucolytic or antitussive effect in a patientin need of such effect, said method comprising administering to saidpatient a therapeutically effective amount of a compound of claim 1.